A hallmark of thymus-dependent (TD) humoral immunity is its longevity. This longevity is manifested by the durability of the memory B cell (Bmem) and plasma cell (PC) compartments. Studies are presented to gain an understanding of the factors that control the generation and survival of Bmem, plasma cell precursors (PrePC) and PCs in immunity and autoimmunity. The specific aims are: 1. To define memory B cell (Bmem) subsets and determine the immunologic mediators that govern their generation, survival, and differentiation. We hypothesize that the immune environment (antigen, cytokines and nature of TLR agonists) can qualitatively and quantitatively change the balance of Bmem vs. PC. In addition, antigen, bystander T cell help and TLR agonists may play a seminal role in the survival of Bmem. Furthermore, new data is presented that the BAFF/Blys pathway may regulate Bmem homeostasis. Finally, the fate of Bmem and their differentiation into longlived or short-lived PCs will be determined. 2. To ascertain the cellular and molecular requirements for PrePC survival, selection and differentiation in the BM. We have identified a rapidly growing, self-renewing, post-GC B cell in the BM that gives rise to PC. This specific aim will address the role the bone marrow elements play in the survival, function and self-renewing capacity of the PrePC. In addition, we have shown that antigen can enhance the selection of PrePC resulting in the production of higher affinity PCs. The basis for the affinity selection of PrePC within the BM will be investigated. 3. To identify elements within the BM microenvironment that are involved in the survival of PCs. We envision the immune BM as a dynamic and unique niche that fosters the differentiation of PrePC to PCs. Once generated, PCs perist in the BM for long periods of time. We show that Class II MHC+ cells are critical for PC survival and more specifically, the Blys/BAFF pathway is critical for PC persistence in vitro and in vivo. We present a hypothesis that BAFF+, Class II+ cells in the BM support PC survival. Given this observation, cellular and molecular studies on the role of the receptor for BAFF (likely BCMA), in PC survival are proposed. 4. To define alterations in the homeostasis of Bmem and long-lived PCs in autoimmunity. The chronic generation of autoreactive Bmem and the production of autoantibodies by long-lived PCs are likely central to the pathogenesis of lupus and other antibody-mediated autoimmune diseases. Data show that, in addition to long-lived BM PCs, autoantibody-producing PCs can be found in inflamed tissue. We will determine the factors that are critical for PC migration and survival in inflamed tissue in lupus-prone strains of mice. Furthermore, we will investigate if the combination of therapeutics that intervene in immune activation, and those that facilitate the decay of long-lived PCs can synergistically enhance disease-free survival of lupus prone mice.